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Quality of life in survivors of oropharyngeal cancer: A systematic review and meta-analysis of 1366 patients

European Journal of Cancer, Volume 78, June 2017, Pages 91-102

Abstract

Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is rapidly increasing in incidence and has a favourable prognosis compared with HPV-negative disease. Current combined therapies include significant risks of morbidity for the growing group of survivors. This systematic review and meta-analysis investigates how treatment affects quality of life (QoL) in survivors of oropharyngeal cancer. PubMed, EMBASE and the Cochrane Library were systematically searched for all studies reporting patient-assessed QoL at least 1 year after treatment for OPC. In a meta-analysis, weighted average QoL scores from the four most commonly utilised QoL instruments were compared with baseline and reference group scores using the concept of minimal clinically important difference. The meta-analysis included data from 1366 patients from 25 studies and 12 countries. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) was answered by 704 patients, 644 patients answered the EORTC QLQ Head and Neck-35 (H&N-35), 474 patients answered the University of Washington Quality of Life Questionnaire, and 381 patients answered the M. D. Anderson Dysphagia Inventory. Moderate to large clinically important deteriorations in QoL were found in the domains dry mouth and sticky saliva for the EORTC QLQ-H&N35, saliva, chewing, swallowing, speech, taste, appearance and shoulder for the University of Washington Quality of Life Questionnaire, and the global, physical and emotional subscales for the M. D. Anderson Dysphagia Inventory. In conclusion, survivors of OPC face clinically important deteriorations in QoL that most markedly centre on xerostomia, dysphagia and chewing. These ailments indicate a potential for improvement in patient management.

Highlights

  • Survivors of oropharyngeal cancer face impairments in quality of life.
  • Clinically important deteriorations centre on xerostomia, dysphagia and chewing.
  • There is room for improvement in the management of oropharyngeal cancer.
  • The use of identical quality of life instruments could benefit research.

Keywords: Oropharyngeal cancer, Quality of life, Long-term effects, Survivors, Review.

1. Introduction

In recent decades, the Western world has experienced a marked increase in the incidence of oropharyngeal cancer (OPC) [1], [2], and [3], and epidemiological research has attributed this rise to a slow epidemic of human papillomavirus (HPV)-induced tumours [4] and [5]. The growing group of HPV-positive patients distinguishes itself from the traditional group of patients with tobacco- and alcohol-related disease (HPV-negative) by being younger and less comorbid, and by responding favourably to treatment [6], [7], [8], and [9]. In spite of this, the nodal stage of HPV-positive disease often mandates intensified treatment by radiation and possibly concurrent chemotherapy, with the risk of serious sequelae such as dysphagia and xerostomia [10], [11], and [12]. Consequently, patients treated for HPV-associated disease potentially face decades of survival with a severely impaired quality of life (QoL) [13]. This prospect has challenged the existing treatment paradigms in OPC, prompting suggestions from treatment de-intensification for low-risk HPV-positive patient subgroups, to the implementation of a separate TNM classification system for HPV-positive disease [6], [14], and [15]. In order for patients and clinicians to make an informed decision regarding future treatment options, they require knowledge as to how contemporary therapies affect the QoL of OPC survivors. To date, the available literature for OPC alone has not been systematically reviewed.

The QoL of head and neck cancer patients deteriorates immediately after treatment and then gradually approaches pre-treatment conditions, becoming stable approximately 12 months after treatment [16], [17], [18], and [19]. Because of this, some studies present follow-up data on QoL from 1 year after therapy and onwards without stratification [18], [20], and [21]. To meaningfully interpret QoL scores, the magnitude of change in QoL that is perceptible to the individual patient must be approximated [22]. To this end, the minimal clinically important difference (MCID) has been defined as ‘the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient's management’ [23].

In this article, we systematically review the current literature on patient-reported QoL at follow-up at least 1 year after treatment for OPC and perform a meta-analysis to determine which QoL domains are most clinically importantly affected by treatment.

2. Materials and methods

This systematic review and meta-analysis was conducted with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [24].

2.1. Systematic literature search and eligibility criteria

Two authors (SHM and JHM) systematically searched the PubMed, EMBASE and Cochrane Library databases for English, German and Scandinavian language articles based on a Population, Intervention, Comparison, Outcome and Study design strategy (Appendix A) [25]. The search was last updated on July 20th, 2016. The target population consisted of patients treated for OPC, and the intervention was the assessment of QoL by a patient-reported, formally developed, validated QoL questionnaire at least 1 year after the treatment. The intention was a fourfold comparison consisting of QoL: pre-treatment versus at follow-up, at follow-up versus the general population, at follow-up in patients with HPV-positive versus HPV-negative disease and at follow-up following primary surgery versus primary radiation-therapy. The outcome measure was numerically reported mean or median values for QoL at follow-up. Accepted study designs consisted of intervention or observational studies including at least 12 OPC patients. Studies comprising head and neck cancer populations were only included if they provided separate data on OPC patients. In case of overlapping reports on the same patient cohort, only the studies with the longest follow-up were included. Studies on non-squamous cell carcinomas were excluded. No restrictions regarding publication date, gender, age or ethnicity were imposed. Any discrepancies regarding study eligibility were solved through discussion. Fig. 1 depicts the systematic identification of studies [24].

Fig. 1

Fig. 1

PRISMA study selection flowchart.

 

2.2. Data extraction and quality assessment/risk of bias

One reviewer (SHM) recorded all baseline and follow-up QoL scores, as well as clinicopathological and demographic data. The four most commonly appearing QoL instruments were identified, and from these, only studies providing mean scores were included in the meta-analysis (Table 1). The methodological quality of each study in the meta-analysis was cross-checked by two reviewers (SHM and JHM) using a 14-item checklist of predefined criteria (Appendix B) [26] and [27].

Table 1

Patient and disease characteristics for QoL instruments in the meta-analysis.

 

Patient and disease characteristics
QLQ-C30 [21], [40], [41], [42], [43], [56], [66], [74], [77], and [78] QLQ-H&N35 [21], [40], [41], [42], [43], [56], [66], [77], and [78] UW-QOL [48], [49], [63], [64], [76], [79], [80], [81], [82], [83], and [84] MDADI [20], [47], [63], [75], [76], [81], [82], [84], and [85]
Respondents at follow-up 704 Respondents at follow-up 644 Respondents at follow-up 474 Respondents at follow-up 381
Max. no. per subscale 704 Max. no. per subscale 644 Max. no. per domain 387 Max. no. per subscale 381
Min. no. per subscale 528 Min. no. per subscale 434 Min. no. per domain 134 Min. no. per subscale 273
Follow-up (months) 12–200 Follow-up (months) 12–200 Follow-up (months) 12–312 Follow-up (months) 12–165
Inclusion period 1981–2011 Inclusion period 1990–2011 Inclusion period 1993–2013 Inclusion period 1999–2011
Median agea 56–61 Median agea 56–61 Median agea 45–58 Median agea 57
Mean agea 57–59.7 Mean agea 57–59.7 Mean agea 45.7–53 Mean agea 57–66
Male 407 Male 367 Male 272 Male 154
Female 129 Female 109 Female 64 Female 34
Only baseline datab 63 Only baseline data 63 Only baseline data 47 Only baseline data 145
Not specified 105 Not specified 105 Only mix. cancer gender 91 Only mix. cancer gender 48
Surgery ± adjuvant 227 Surgery ± adjuvant 207 Surgery ± adjuvant 298 Surgery ± adjuvant 163
 S only 33  S only 33  S only 11  S only 21
 S + RT 151  S + RT 131  S + RT 200  S + RT 77
 S ± RT 43  S ± RT 43  S + CRT 23  S + CRT 18
 S ± RT 64  S+(C)RT 47
Non-surgical treatment 414 Non-surgical treatment 374 Non-surgical treatment 129 Non-surgical treatment 171
 RT only 91  RT only 58  RT only 3  RT only 12
 CRT 67  CRT 60  CRT 59  CRT 34
 BT ± RT 49  BT ± RT 49  C-IMRT 40  (C)-RT 98
 (C)-IMRT 207  (C)-IMRT 207  (C)-IMRT 27  (C)-IMRT 27
Only baseline data 63 Only baseline data 63 Only baseline data 47 Only baseline data 47
TNM III + IV 213 TNM III + IV 173 TNM III + IV 204 TNM III + IV 142
I + II 38 I + II 18 I + II 7 I + II 23
Mix. cancer onlyc 27 Mix. cancer only 27 Mix. cancer only 27 Mix. cancer only 27
Baseline only 63 Baseline only 63 Not specified 236 Baseline only 98
Not specified 363 Not specified 363 Not specified 91
HPV Not specified 704 HPV Not specified 644 HPV Positive 79 HPV Positive 39
Negative 22 Negative 18
Not specified 373 Not specified 324

a Range of available data from single studies.

b Gender composition for respondents at follow-up not specified.

c Clinicodemographics not separately specified for oropharyngeal patients in mixed cancer cohort.

Abbreviations: S, surgery; RT, radiotherapy; CRT, chemo-radiotherapy; BT, brachytherapy; (C) = ±chemotherapy; IMRT, intensity-modulated radiotherapy; HPV, HPV or p16.

2.3. QoL instruments in the meta-analysis

The University of Washington Quality of Life Questionnaire (UW-QOL) is specific to head and neck cancer [28]. Scores range from 0 to 100 with higher scores being favourable.

The M. D. Anderson Dysphagia Inventory (MDADI) assesses the effect of dysphagia on QoL in head and neck cancer patients. Scores range from 20 to 100 with higher scores being favourable [29].

The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Head and Neck-35 (QLQ-H&N35) evaluates the impact of head and neck cancer on QoL on a scale from 0 to 100 [30]. A high score represents more problems and is unfavourable.

The EORTC QLQ Core-30 (QLQ-C30) is a general cancer questionnaire not specific to head and neck cancer [30]. It is scored on a scale from 0 to 100. A high score for a functional or global health scale is favourable, whereas a high score for a symptom scale is unfavourable.

2.4. Calculating the minimal clinically important difference (MCID)

The MCID can be approximated in several ways [31] and [32]. Due to an inconsistent reporting of statistical variance among studies in the meta-analysis, we adopted the same rule of thumb as most of the included studies, namely that a 10% change of the maximal instrument score corresponds to the MCID [33]. Though crude, this estimate has been repeatedly substantiated in the literature [34], [35], and [36].

2.5. Reference values

For the UW-QOL, we used the recommended non-stratified reference data from non-cancer patients aged 40–79 attending routine dental appointments [37] and [38]. For the MDADI, the reference population consisted of the non-dysphagic control group from the Swedish validation study of the questionnaire [39]. For the QLQ-H&N35, the weighted mean of all available baseline scores from included studies served as a reference [40], [41], [42], and [43]. For the QLQ-C30, European general population normative values for men in the age-group 50–59 years were utilised as a reference [44]. Baseline respondents served as a reference for the assessment of change in QoL over time.

2.6. Heat map analysis

We conducted a heat map analysis to illustrate the degree of clinically important difference between follow-up scores and reference scores (Table 2 and Table 3) [45] and [46]. Although an MCID is often estimated as 10% of the maximal instrument score, there is no consensus as to what constitutes a moderate or large clinically important difference [33]. Prior studies have defined moderate clinically important differences as 12–21% of the instrument range and large clinically important differences above this [35]. In our heat map analysis, clinically important differences are presented in intervals of 10% of the maximal instrument score. For each domain, the relative QoL difference was calculated as the absolute difference between the QoL score at follow-up and the reference score, divided by the MCID. We refer to differences in QoL constituting 10–19.9% of the maximal instrument score as minimal (ratio 1.00–1.99), 20–29.9% differences as moderate (ratio 2.00–2.99), and ≥30% differences as large clinically important differences (ratio ≥3.00). To ease interpretation, ratios that designate improvements in function have been assigned positive values, whereas negative values designate deteriorations.

Table 2

Heat map for the UW-QOL and the MDADI.

 

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Table 3

Heat map for the QLQ-C30 and QLQ-H&N35.

 

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All calculations were conducted in Apache OpenOffice Calc version 4.1.1.

3. Results

3.1. Literature search result

The literature search generated 4959 citations of which 41 studies were included in the qualitative synthesis (Fig. 1). Among the studies reporting mean scores, the four most frequently utilised QoL instruments were included in the meta-analysis. This amounted to 39 QoL questionnaires from 25 different studies, based in 12 countries, and published no earlier than 1997. In total, 474 patients answered the UW-QOL, 381 patients answered the MDADI, 644 patients answered the QLQ-H&N35 and 704 patients answered the QLQ-C30. Some patients answered more than one questionnaire: 193 patients answered both the UW-QOL and the MDADI, and 644 patients answered both of the EORTC questionnaires.

3.2. Meta-analysis results

Numerical QoL scores and the corresponding study characteristics are presented in Appendix C–G.

3.3. Patient characteristics

The majority of questionnaire respondents at follow-up were male (78% of 1536 questionnaires) and had advanced stage disease at presentation. Patient follow-up ranged from 1 to 26 years, and the mean age at diagnosis ranged from 45.7 to 66 years (Table 2). Eleven studies did not report clinicopathological and demographic data corresponding to the actual number of questionnaire respondents at follow-up, but instead reported only baseline or mixed cancer cohort data (n = 691 questionnaires, 31%). It was not possible to undertake a sub-analysis of patients with HPV-associated disease, since the three studies that reported on HPV or its marker, p16, did not mention HPV in correlation analyses [47], [48], and [49].

3.4. Methodological quality

The methodological quality of the 25 studies ranged from eight to 14 points with an average high-quality score of 11.4 (Appendix B).

3.5. QoL according to the UW-QOL

Compared to the normative reference population of dental patients, the weighted average UW-QOL scores at follow-up for OPC survivors showed minimal clinically important deteriorations for the domains of activity and recreation, moderate clinically important deteriorations with regard to physical function, composite QoL score, appearance, swallowing, speech, shoulder and taste and large clinically important deteriorations in the domains for chewing and saliva (Table 2). The greatest inter-study difference was found in the chewing domain, and the smallest in the social-emotional summary score (Fig. 2). The available data did not allow for sub-analysis based on treatment method, and there were not enough pre-treatment respondents to assess the change in QoL over time.

Fig. 2

Fig. 2

Single-study quality of life (QoL) graphed alongside weighted average QoL and reference group QoL. The dashed line indicates the level below which functional scores/above which symptom scores are minimally clinically importantly worse than reference scores.

 

3.6. QoL according to the MDADI

Compared to the non-dysphagic reference, average MDADI scores at follow-up for OPC survivors presented a minimal clinically important deterioration in the functional subscale, moderate clinically important deteriorations in composite score, global and emotional subscales and a large clinically important deterioration in the physical subscale (Table 2). The global domain showed the greatest inter-study difference and the physical domain the smallest. The available data were not sufficient for sub-analysis pertaining to treatment method, and there were not enough pre-treatment respondents to assess the change in QoL over time.

3.7. QoL according to the QLQ-H&N35

Compared with pre-treatment reference values, the average QLQ-H&N35 scores at follow-up for OPC survivors showed minimal clinically important deteriorations with regard to senses, social eating, teeth and opening mouth, a moderate clinically important deterioration with regard to sticky saliva and a large clinically important deterioration for dry mouth. Head and neck pain (mouth, jaw and throat pain) showed a minimal clinically important improvement at follow-up (Table 3). The greatest inter-study difference was found in the subscale for less sexuality, and the smallest was found in the single-item weight gain (Fig. 2). Due to insufficient data, a pre-treatment reference could not be created for pain killers, nutritional supplements, feeding tube, weight loss, and weight gain (Appendix G).

Dichotomisation of EORTC scores into categories of ‘non-surgical treatment’ versus ‘primary surgery with or without adjuvant treatment’ showed an MCID in favour of surgical treatment for the QLQ-H&N35 single-item nutritional supplements (66 non-surgical respondents, score 33.8 versus 125 surgical respondents, score 20.8). Stratification on the basis of TNM classification or adjuvant chemotherapy was not possible.

3.8. QoL according to the QLQ-C30

Compared to the general population, the average QLQ-C30 score for physical functioning, fatigue and appetite loss showed a minimal clinically important deterioration in OPC survivors at follow-up (Table 3). The greatest inter-study difference was found in the sleep disturbance/insomnia subscale, and the smallest in the nausea/vomiting subscale (Fig. 2). Compared with pre-treatment QoL, the QLQ-C30 could detect no clinically important changes at follow-up. Patients on average rated their global QoL almost similarly to pre-treatment and not clinically importantly different from the general population.

4. Discussion

To our knowledge, we present the first systematic review on QoL at least 1 year after treatment for OPC. The most conspicuous impairments in QoL at follow-up were seen in domains related to eating, both compared with non-OPC reference populations and to pre-treatment scores. Deteriorations in average QoL scores were most profound in UW-QOL saliva, chewing, swallowing, speech, taste, appearance and shoulder, in MDADI physical, global and emotional subscales and in QLQ-H&N35 dry mouth and sticky saliva. We found that the QLQ-C30 non-specific, global QoL score in OPC survivors was not clinically importantly worse than the global QoL score for the general population.

The tendency for patient-rated, non-specific, global QoL to plateau at values not clinically importantly different from reference scores, despite clinically important deteriorations in individually specified domains, has been explained by the concept of ‘response shift’. This term is defined as the subjective reconceptualisation of life quality, the recalibration of internal standards of measurement or the reprioritization of QoL domains that occurs in patients over the course of a disease [50]. According to a recent study, non-specific global QoL scores should not be considered equivalent to the sum of individual domain scores, as the latter appear to be less susceptible to response shift [51]. Therefore, while it is encouraging that a subjectively normal global QoL can be attained in survivors of OPC, individual domain scores still show room for improvement. This claim is substantiated by the statistic that the incidence of suicide among patients with cancer of the oropharynx or oral cavity is five times that of the general US population [52].

The heat map analysis revealed discrepancies between equally named domain scores from different QoL instruments. This issue highlights some of the general challenges of measuring and interpreting QoL scores. First, both the content and quantity of questions on which equally named domain scores are based vary notably between questionnaire types. For instance, ‘global QoL’ in the QLQ-C30 refers to patient-rated overall health and QoL during the past week, whereas the MDADI ‘global’ score refers to the extent to which swallowing ability limits day-to-day activities [29]. Second, results should be interpreted with respect to their reference populations. For instance, patients recently diagnosed with OPC potentially suffer from tumour-related symptoms and a high level of emotional distress at baseline [43] and [53]. Consequently, a return to pre-treatment QoL levels does not signify a return to pre-disease QoL [54]. In lieu of unobtainable pre-disease references, control group or general population references offer a useful alternative [55]. Some studies have also used external factors such as employment or the resumption of professional activity as an aid in the interpretation of QoL scores [21] and [56].

The inclusion periods of most studies pre-dated consistent HPV testing. Out of the 41 studies in the qualitative synthesis, only nine provided HPV/p16 data. Two of these studies found no correlation between HPV-status and QoL domains one year post-treatment [57] and [58], two studies with follow-up periods beyond 1 year and a smaller proportion of smokers among HPV-positive patients found statistically significantly better QoL outcomes in HPV-positive disease at follow-up [59] and [60], and five studies did not mention HPV-status in correlation analyses [47], [48], [49], [61], and [62]. Due to this scarcity of information, no conclusion could be approximated regarding the influence of HPV-status on QoL.

Due to the potentially confounding effect of variables such as tumour stage and co-morbidity, QoL outcomes between different treatment modalities cannot be directly compared [21], [63], and [64]. With this in mind, the meta-analysis showed that average QoL scores at least 1 year after primary surgery were largely comparable to scores at least 1 year after organ-preservation strategies. This was an expected outcome, seeing as the vast majority of surgically treated patients were also irradiated [65]. The meta-analysis contained sparse data on patients treated by primary surgery without any adjuvant treatment, but the qualitative synthesis contained examples of these patients achieving better QoL at follow-up than patients receiving adjuvant treatment [58], [59], [66], [67], and [68].

In the context of the prolonged survival of patients with HPV-positive disease, newer studies have suggested a potential for minimally invasive transoral robotic surgery (TORS) to offer de-escalation or even complete avoidance of postoperative adjuvant treatment to select low-risk patients [67] and [69]. Although there is a paucity of literature describing long-term QoL after TORS, two recent reviews tentatively suggest that TORS may decrease post-treatment swallowing impairment in OPC [70] and [71]. The coming years will bring much-needed knowledge from randomised, multi-centre trials on transoral surgery and treatment de-escalation in HPV-positive disease (PATHOS, E3311), as well as on transoral surgery versus non-surgical management in disease stratified by HPV status (ORATOR) [72]. In addition to this, non-surgical treatment options are evolving, and OPC patients with tumour tissue available for HPV testing are currently being recruited for a trial comparing intensity-modulated proton beam therapy to IMRT (NCT01893307). A standardisation of QoL registration would facilitate inter-study QoL comparisons in the evaluation of such new therapies.

There were several limitations to this review. Many studies excluded patients with recurrence or a new primary, which could have inflated QoL scores [56]. The variations in choice of QoL instruments limited the number of studies available for comparison, many sample sizes were small and response rates at follow-up were often low. There were notable imbalances in baseline characteristics across series, and the lack of specific patient and disease characteristics for respondents as opposed to non-respondents at follow-up made desirable stratifications infeasible. Seeing as some patients were treated as early as 1981, certain QoL results may reflect the use of historical regimens that are no longer conventionally used, just as the fraction of HPV-positive patients is likely to have increased over time [73] and [74]. Finally, QoL 12 months post-treatment is not a perfect indicator of long-term QoL. For instance, one of the included studies found that swallowing function was on an upward trajectory by 12 months, and another found a pattern of declining function from 6 months to 2 years [75] and [76].

Future randomised prospective trials should accommodate inter-trial comparisons by using similar protocols and identical head and neck-specific QoL instruments. Both mean and median scores should be reported. Including the UW-QOL would allow for a differentiation between health-related and overall QoL, the QLQ-H&N35 would allow for an evaluation of social eating and sexuality, and the MDADI would allow for a suitable focus on the key problem of dysphagia. To minimise the influence of response shift, all individual domain scores should be reported. Furthermore, comparisons with control group or population norms should be incorporated as a perspective on the potential for long-term improvement. Optimally, follow-up should continue past 12 months and include HPV status as a stratification factor.

In conclusion, QoL at least 1 year after treatment for OPC is compromised by several clinically important problems centred on xerostomia, dysphagia and chewing. Patients nevertheless show a capacity for achieving a self-rated global QoL comparable to that of the general population, potentially because of response-shift. As of yet, there is insufficient evidence in the literature to meta-analyse the role of HPV-positivity on QoL. Inter-study comparisons are currently restricted by the heterogeneity of disease parameters, treatment methods and outcome measures, but randomised, multi-centre trials are being established that stratify patients based on HPV-status and include QoL as an endpoint in the evaluation of treatment modalities.

Role of the funding source

The two non-profit organisations funding CGL had no involvement in any part of this work.

Conflict of interest statement

None declared.

Funding

CGL is supported by the non-profit Candy's Foundation [no grant number] and Kræftfonden (The Cancer Foundation) [no grant number].

Appendix A. Supplementary data

The following is the supplementary data related to this article:

mmc1

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Footnotes

a Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark

b Department of Oncology, University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark

Corresponding author.


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